The present invention relates to the use of amtolmetin guacyl for the production of an anti-inflammatory drug for intestinal inflammations. In the present description amtolmetin guacyl, whose chemical name is 2-metoxyphenyl-1-methyl-5-p-methylbenzoyl-pirrol-2-acetamido acetate, will be also referred to as MED 15.
Inflammation is a primary pathological process involving the passage of the neutrophilic leukocytes through vasal endothelium directed towards the inflamed tissue (1).
The arachidonic acid metabolites have been linked to several inflammatory diseases, including psoriasis (2,3) rheumatoid arthritis (4), asthma (5-8), multiple sclerosis (9), uveitis and IBD (10-14). Prostaglandin can play a role in the inflammatory process, enhancing vasodilatation and formation of oedema; on the other hand lipoxygenase products, in particular LTB4, exert a potent stimulating action on leukocytes: evidence supporting the importance of such metabolites comes from the observation of their increase in the inflamed colon mucus (15-16).
IBD aetiology is obscure, the hypothesised causative agents being antigens of bacterial origin, alimentary intolerance and a defective intestinal barrier. More recently the role of vascularization in Crohn""s disease has been further emphasised. Although the IBD triggering event remains unknown, both ulcerative colitis and Crohn""s disease in active phase are associated with a non-specific inflammatory reaction, and are characterised by chronic inflammation with overlapping acute inflammatory exacerbation. At the chronic stage macrophages and lymphocytes infiltrate the intestine, whereas in the acute stage the cells migrating in the intestinal mucus are the neutrophils and perhaps the eosinophils.
At present a resolutive therapy for these pathologies is unavailable: the cycloxygenase-inhibiting NSAIDs (17,18) commonly used in the treatment of inflammatory pathologies, not only do not yield an improvement in the disease, but can even cause recurrences in patients in inactive phase. At present, drugs used for the therapy of colitis are corticosteroids, sulfasalazine and 5-ASA. Corticosteroids exert their anti-inflammatory action through the release of a PLA2 endogenous inhibitor named macrocurtain or lipocurtain (19), but possess other biological properties as well, that can be related to their therapeutical effects on IBD: on lymphocyte differentiation, cytokine synthesis and interferon production (20). However, the pharmacological characteristic/property underlying the effectiveness of corticosteroids remains undetermined.
Sulfasalazine and 5-ASA can reduce the inflammation acting as inhibitors of PAF, interleukin 1, TNF, MPO and thus acting as scavengers of the free radicals (21). Hence, as it is the case for corticosteroids, also sulfasalazine and 5-ASA possess other pharmacological properties, unrelated to the eicosanoid production, and for such drugs as well the pharmacological properties underlying their effectiveness is still undetermined.
However, all of these drugs entail serious side-effects that markedly restrict their use in long-term therapies. Therefore it would be desirable to find a product that is both effective for this pathology and devoid of side-effects.
MED 15 is a powerful non-steroidal anti-inflammatory drug (in short NSAID in the following) as amply reported in literature (22-23). Med 15 is the subject matter of the Italian patent IT 1210673. In this regard however, it has to be pointed out that the NSAIDs commonly used as antipyretic, analgesic and anti-inflammatory in a wide spectrum of pathologies, ranging from chronical pain to post-surgery pains to muscular-scheletric pains, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, to menstrual pains (consequent to prostaglandin release), are well-known to be gastrolesive, in particular at the enteric level.
The present invention is based on the discovery that MED 15 is a NSAID that can be successfully used in Crown""s disease, as well as in all intestinal inflammations, in particular colitis with an underlying auto-immune component. Actually, there is experimental evidence proving the protective action exerted by MED 15 on the enteric mucus, in which a marked presence of the intact (i.e., not metabolised) MED 15 molecule was demonstrated, a requirement for ascribing to it a protective effect.
The MED 15 molecular structure includes a vanillic radical responsible for the stimulation of the stomach and intestine capsaicin receptors (24). At the gastric level these receptors are physiologically related to the CGRP neuropeptide, with which they interact for the down-regulation of the acid secretion (25-28); whereas the capsaicinic receptors of the intestine are related to another neuropeptide, VIP, in order to protect the intestinal mucus (29).
VIP (Vasoactive Intestinal Peptide) is a 28 amino acid peptide which is localised in both the central and peripheral nervous system. VIP has various effects on intestinal functions:
1) it stimulates mucosal water, electrolyte and mucus secretion;
2) it is a potent stimulant of duodenal HCO3 secretion;
3) it s involved in peristaltic reflex;
4) it inhibits absorption and has a predominant relaxation action;
5) it plays an inhibitory role on immune cell function.
Several studies demonstrated a decrease of VIP intestinal mucosal content in patients with ulcerative colitis and this alteration seems to be correlated to the degree of mucosal inflammation (see J. Physiol Paris Sorrenti et al 1993; 87(5):307-311).
The released CGRP passes into the bloodstream and reaches other districts, exerting its vasodilator effect. The above mentioned neuropeptides, interacting with the capsaicinic receptors in the two different sites of the gastroenteric apparatus, are responsible of the protective action exerted by MED 15 on the mucus; such effect is obtained at the gastric level by direct action of the CGRP and consequently by NO deriving therefrom (30,31), whereas at the intestinal level VIP acts autonomously, since, unlike CGRP, it does not stimulate NO synthetase. Therefore the action of MED 15 on intestinal inflammation is carried out through the production of VIP, induced by the administration of same MED 15.
In light of the aforementioned it is apparent that in order to obtain a maximum therapeutical effectiveness MED 15 ought to be intaken with an empty stomach to allow saturation of the capsaicinic receptors. Furthermore, on the basis of this mechanism, the need to avoid contemporary intake of anti-H1 drugs (32), known to interfere with the capsaicinic receptors, should be taken into account.
Concerning the MED 15 vasodilator effect, that can be referred as to its mechanism to the CGRP production, it has been previously reported and is incorporated in the present description with reference to the application PCT/IT97/00209.
Therefore, an object of the present invention is the use of MED 15 for the production of an anti-inflammatory drug for intestinal inflammations.